Myocardial perfusion imaging method

ABSTRACT

A myocardial imaging method that is accomplished by administering one or more adenosine A 2A  adenosine receptor agonist to a human undergoing myocardial imaging.

BACKGROUND OF THE INVENTION

[0001] This application claims the benefit of U.S. Provisional PatentApplication Nos. 60/399177, filed on Jul. 29, 2002, 60/399176 filed onJul. 29, 2002, 60/426902 filed on Nov. 15, 2002 and 60/459803 filed onApr. 2, 2003, the contents of each of which are incorporated herein byreference.

[0002] 1. Field of the Invention

[0003] This invention relates to myocardial imaging methods that areaccomplished by administering doses of one or more adenosine A_(2A)adenosine receptor agonists to a mammal undergoing myocardial imaging.

[0004] 2. Description of the Art

[0005] Myocardial perfusion imaging (MPI) is a diagnostic techniqueuseful for the detection and characterization of coronary arterydisease. Perfusion imaging uses materials such as radionuclucides toidentify areas of insufficient blood flow. In MPI, blood flow ismeasured at rest, and the result compared with the blood flow measuredduring exercise on a treadmill (cardiac stress testing), such exertionbeing necessary to stimulate blood flow. Unfortunately, many patientsare unable to exercise at levels necessary to provide sufficient bloodflow, due to medical conditions such as peripheral vascular disease,arthritis, and the like.

[0006] Therefore, a pharmacological agent that increases cardiac bloodflow (CBF) for a short period of time would be of great benefit,particularly one that did not cause peripheral vasodilation.Vasodilators, for example dipyridamole, have been used for this purposein patients prior to imaging with radionuclide. Dipyridamole is aneffective vasodilator, but side effects such as pain and nausea limitthe usefulness of treatment with this compound.

[0007] Adenosine, a naturally occurring nucleoside, also is useful as avasodilator. Adenosine exerts its biological effects by interacting witha family of adenosine receptors characterized as subtypes A₁, A_(2A),A_(2B), and A₃. Adenoscan® (Fujisawa Healthcare Inc.) is a formulationof a naturally occurring adenosine. Adenoscan® has been marketed as anadjuvant in perfusion studies using radioactive thallium-201. However,its use is limited due to side effects such as flushing, chestdiscomfort, the urge to breathe deeply, headache, throat, neck, and jawpain. These adverse effects of adenosine are due to the activation ofother adenosine receptor subtypes other than A_(2A), which mediates thevasodilatory effects of adenosine. Additionally, the short half-life ofadenosine necessitates multiple treatments during the procedure, furtherlimiting its use. Adenoscan® is contraindicated in many patientsincluding those with second-or third-degree block, sinus node disease,bronchoconstrictive or bronchospastic lung disease, and in patients withknown hypersensitivity to the drug.

[0008] Other potent and selective agonists for the A_(2A) adenosinereceptor are known. For example, MRE-0470 (Medco) is an adenosine A_(2A)receptor agonist that is a potent and selective derivative of adenosine.WRC-0470 (Medco) is an adenosine A_(2A) agonist used as an adjuvant inimaging. In general, compounds such as these have a high affinity forthe A_(2A) receptor, and consequently, a long duration of action, whichis undesirable in imaging.

[0009] Thus, there is still a need for a method of producing rapid andmaximal coronary vasodilation in mammals without causing correspondingperipheral vasodilation, which would be useful for myocardial imagingwith radionuclide agents. Preferred compounds would be selective for theA_(2A) adenosine receptor and have a short duration of action (althoughlonger acting than compounds such as adenosine), thus obviating the needfor multiple dosing.

SUMMARY OF THE INVENTION

[0010] The following are several aspects of this invention.

[0011] A method of producing coronary vasodilation without peripheralvasodilation in a human, comprising administering at least 10 μg of atleast one A_(2A) receptor agonist to the human.

[0012] A method of producing coronary vasodilation without peripheralvasodilation in a human, comprising administering no more than about1000 μg of a A_(2A) receptor agonist to the human.

[0013] A method of producing coronary vasodilation without peripheralvasodilation in a human, comprising administering a A_(2A) receptoragonist in an amount ranging from about 10 to about 600 μg to the human.

[0014] A method of producing coronary vasodilation without peripheralvasodilation in a human, comprising administering about 300 μg of aA_(2A) receptor agonist to the human.

[0015] A method of producing coronary vasodilation without peripheralvasodilation in a human, comprising administering about 400 μg of aA_(2A) receptor agonist to the human. 30 A method of producing coronaryvasodilation without peripheral vasodilation in a human, comprisingadministering about 500 μg of a A_(2A) receptor agonist to the human.

[0016] A method of producing coronary vasodilation without peripheralvasodilation in a human, comprising administering about 600 1g of aA_(2A) receptor agonist to the human.

[0017] A method of producing coronary vasodilation without peripheralvasodilation in a human, comprising administering about 700 μg of aA_(2A) receptor agonist to the human.

[0018] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is administered in an amount ranging from about10 to about 600 μg and wherein the A_(2A) receptor agonist isadministered in a single dose.

[0019] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein about300 μg of the A_(2A) receptor agonist is administered in a single dose.

[0020] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein about400 μg of the A_(2A) receptor agonist is administered in a single dose.

[0021] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein about500 μg of the A_(2A) receptor agonist is administered in a single dose.

[0022] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein about600 μg of the A_(2A) receptor agonist is administered in a single dose.

[0023] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein about700 μg of the A_(2A) receptor agonist is administered in a single dose.

[0024] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is administered in an amount ranging from about10 to about 600 μg and wherein the A_(2A) receptor agonist isadministered by iv bolus.

[0025] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is administered in an amount ranging from about0.05 to about 60 μg/kg and wherein the A_(2A) receptor agonist isadministered by iv bolus.

[0026] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is administered in an amount ranging from about0.1 to about 30 μg/kg wherein the A_(2A) receptor agonist isadministered by iv bolus.

[0027] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is administered in an amount no greater thanabout 20 μg/kg to a supine patient wherein the A_(2A) receptor agonistis administered by iv bolus.

[0028] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is administered in an amount no greater thanabout 10 μg/kg to a standing patient wherein the A_(2A) receptor agonistis administered by iv bolus.

[0029] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is administered in an amount ranging from about10 to about 600 μg wherein the wherein the A_(2A) receptor agonist isadministered in about 20 seconds.

[0030] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist in an amountranging from about 10 to about 600 μg wherein the A_(2A) receptoragonist is administered in less than about 10 seconds.

[0031] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is administered in an amount greater than about10 μg.

[0032] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is administered in an amount greater than about100 μg.

[0033] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is administered in an amount no greater than 600μ.

[0034] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is administered in an amount no greater than 500μg.

[0035] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is administered in an amount ranging from about100 μg to about 500 μg.

[0036] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theA_(2A) receptor agonist is selected from the group consisting ofCVT-3033, CVT-3146 and combinations thereof.

[0037] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and about 300 μg of a compound selectedfrom the group consisting of CVT-3033, CVT-3146 to the human.

[0038] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and about 400 μg of a compound selectedfrom the group consisting of CVT-3033, CVT-3146 to the human.

[0039] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and about 500 μg of a compound selectedfrom the group consisting of CVT-3033, CVT-3146 to the human.

[0040] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and about 600 μg of a compound selectedfrom the group consisting of CVT-3033, CVT-3146 to the human.

[0041] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and about 700 μg of a compound selectedfrom the group consisting of CVT-3033, CVT-3146 to the human.

[0042] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein themyocardium is examined for areas of insufficient blood flow followingadministration of the radionuclide and the A_(2A) receptor agonist.

[0043] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein themyocardium is examined for areas of insufficient blood flow followingadministration of the radionuclide and the A_(2A) receptor agonistwherein the myocardium examination begins within about I minute from thetime the A_(2A) receptor agonist is administered.

[0044] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theadministration of the A_(2A) receptor agonist causes at least a 2.5 foldincrease in coronary blood flow.

[0045] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theadministration of the A_(2A) receptor agonist causes at least a 2.5 foldincrease in coronary blood flow that is achieved within about 1 minutefrom the administration of the A_(2A) receptor agonist.

[0046] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theradionuclide and the A_(2A) receptor agonist are administeredseparately.

[0047] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theradionuclide and the A_(2A) receptor agonist are administeredsimultaneously.

[0048] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theadministration of the A_(2A) receptor agonist causes at least a 2.5 foldincrease in coronary blood flow for less than about 5 minutes.

[0049] A method of myocardial perfusion imaging of a human, comprisingadministering a radionuclide and a A_(2A) receptor agonist wherein theadministration of the A_(2A) receptor agonist causes at least a 2.5 foldincrease in coronary blood flow for less than about 3 minutes.

[0050] A method of myocardial perfusion imaging of a human, comprisingadministering CVT-3146 in an amount ranging from about 10 to about 600μg in a single iv bolus.

[0051] A method of myocardial perfusion imaging of a human, comprisingadministering CVT-3146 in an amount ranging from about 100 to about 500μg in a single iv bolus.

[0052] A method of myocardial perfusion imaging of a human comprisingadministering CVT-3 146 by iv bolus in an amount ranging from 10 toabout 600 μg that is independent of the weight of the human being dosed.

[0053] In all of the methods above, the dose is preferably administeredin a single dose.

[0054] In all of the methods above, at least one radionuclide isadministered before, with or after the administration of the A_(2A)receptor agonist to facilitate myocardial imaging.

[0055] In all of the methods above, the dose is preferably administeredin 60 seconds or less, preferably 30 seconds or less, and morepreferably 20 seconds or less.

DESCRIPTION OF THE FIGURES

[0056]FIG. 1 are intracoronary Doppler flow profiles followingadministration of 18 μg adenosine IC bolus (top) and 30 μg CVT-3146 IVbolus;

[0057]FIG. 2 is a plot showing the relationship of the dose of CVT-3146on coronary peak flow rates;

[0058]FIG. 3 is a Table that reports the duration of time the coronaryflow velocity is greater than or equal to 2.5 times baseline coronaryflow velocity for varying doses of CVT-3146 wherein “n” refers to thenumber of human patients dosed;

[0059]FIG. 4 is a plot of the time course of the average peak velocity(APV) ratio for human patients receiving 400 μg of CVT-3146 IV bolus;

[0060]FIG. 5 is a plot of the time course of heart rate for humanpatients receiving 400 μg of CVT-3146 IV bolus;

[0061]FIG. 6 is the time course of blood pressure for human patientsreceiving 400 μg of CVT-3146 IV bolus; and

[0062]FIG. 7 is an adverse event Table.

[0063]FIG. 8 is a plot of the change over time of mean CVT-3146 plasmaconcentration in healthy male volunteers in a supine position. Thevarious curves relate to different amounts of CVT-3146 administered tothe patients;

[0064]FIGS. 9 and 10 are plots of the mean change in heart rate ofhealthy male volunteers either in a standing position or in a supineposition over time for various bolus dosing levels of CVT-3146;

[0065]FIG. 11 is a plot of the maximum change in heart rate inrelationship to the total dose of CVT-3146 administered to standing orsupine human male patients. In the plot, the term “DBS” refers to theobserved data point while “fit” refers to a curve fitted to the observeddata points;

[0066]FIG. 12 is a plot of heart rate—(area under curve) AUC(0-15 min)of change from baseline in relationship to the total dose of CVT-3146administered to standing or supine human subjects;

[0067]FIG. 13 is a plot of the maximum change from baseline heart rateat maximum plasma concentration of CVT-3146 for patients in a supineposition;

[0068]FIG. 14 is a plot of heart rate—(area under the curve-time v.effect) AUCE (0-15 min) of change from baseline versus plasma AUC(0-15min) for patients in a supine position;

[0069]FIG. 15 is a plot of the time profiles of mean heart rate changefrom a baseline versus mean plasma concentration over time for a 20μg/kg dose of CVT-3146;

[0070]FIG. 16 is a plot of the average peak to blood flow velocity overtime following administration of CVT-3146 measured at the pulmonaryartery (PA), the four limb artery (FA), brain arterial vasculature (BA)and in the left circumflex coronary artery (LCS);

[0071]FIG. 17 is a plot of the percent change in heart rate (HR) andblood pressure (BP) for various doses of CVC-3146; and

[0072]FIG. 18 is a plot of the change in LBF and RBF blood flow uponadministering increasing amounts of ADO or CVT-3146 to awake dogs.

DESCRIPTION OF THE INVENTION

[0073] Potent A_(2A) agonists are useful as adjuncts in cardiac imagingwhen added either prior to dosing with an imaging agent orsimultaneously with an imaging agent. Suitable imaging agents include²⁰¹Thallium or ^(99m)Technetium-Sestamibi, ^(99mTc)teboroxime, and^(99mTc)(III).

[0074] New and potent A_(2A) agonists that increase CBF but do notsignificantly increase peripheral blood flow have been identified. TheA_(2A) agonists, and especially CVT-3146 and CVT-3033 have a rapid onsetand a short duration when administered. An unexpected and newlyidentified benefit of these new compounds is that they are very usefulwhen administered in a very small quantity in a single bolus intravenous(i.v.) injection. The A_(2A) receptor agonists can be administered inamounts as little as 10 μg and as high as 600 μg or more and still beeffective with few if any side-effects. An optimal dose may include aslittle as 10 μg and as much as about 1000 μg or more of a A_(2A)receptor agonist. More preferably, an optimal dose will range from about100 to about 500 μg of at least one A_(2A) receptor agonist. It ispreferred that the A_(2A) receptor agonist is administered in a singlebolus injection in an amount selected from about 300 μg, about 400 μg,about 500 μg, about 600 μg, and about 700 μg. These amounts areunexpectedly small when compared with adenosine which is typicallyadministered continuously by IV infusion at a rate of about 140μg/kg/min. Unlike adenosine, the same dosage of A_(2A) receptoragonists, and in particular, CVT-3146 and CVT-3033 can be administeredto a human patient regardless of the patient's weight. Thus, theadministration of a single uniform amount of a A_(2A) receptor agonistsby iv bolus for myocardial imaging is dramatically simpler and lesserror prone than the time and weight dependent administration ofadenosine. The dose of A_(2A) receptor agonist administered to a humanpatient can, however, be determined by weight. Typically, a weight baseddose will range from about 0.05 to about 60 μg/kg and more preferablyfrom about 0.1 to about 30 μg/kg. CVT-3 146 in particular is generallywell tolerated when administered in an amount up to 10 μg/kg in standingpatients and up to 20 μg/kg in supine patients.

[0075] A_(2A) agonists of this invention may be administered orally,intravenously, through the epidermis or by any other means known in theart for administering therapeutic agents with bolus i.v. administrationbeing preferred. In one embodiment, the bolus dosing occurs in 60seconds or less. In yet other embodiments, the bolus dosing occurs inabout 30 seconds or less, and more preferably in about 20 seconds orless or in about 10 seconds or less.

[0076] The A_(2A) agonists of this invention are preferably administeredin a single dose. The term “single dose” refers generally to a singlequickly administered dose of a therapeutic amount of at least one A_(2A)receptor agonist. The term “single dose” does not encompass a dose ordoses administered over an extended period of time by, for examplecontinuous i.v. infusion.

[0077] Pharmaceutical compositions including the compounds of thisinvention, and/or derivatives thereof, may be formulated as solutions orlyophilized powders for parenteral administration. Powders may bereconstituted by addition of a suitable diluent or otherpharmaceutically acceptable carrier prior to use. If used in liquid formthe compositions of this invention are preferably incorporated into abuffered, isotonic, aqueous solution. Examples of suitable diluents arenormal isotonic saline solution, standard 5% dextrose in water andbuffered sodium or ammonium acetate solution. Such liquid formulationsare suitable for parenteral administration, but may also be used fororal administration. It may be desirable to add excipients such aspolyvinylpyrrolidinone, gelatin, hydroxy cellulose, acacia, polyethyleneglycol, mannitol, sodium chloride, sodium citrate or any other excipientknown to one of skill in the art to pharmaceutical compositionsincluding compounds of this invention.

[0078] A first class of compounds that are potent and selective agonistsfor the A_(2A) adenosine receptor that are useful in the methods of thisinvention are 2-adenosine N-pyrazole compounds having the formula:

[0079] wherein R¹═CH₂OH, —CONR₅R;

[0080] R³ is independently selected from the group consisting of C₁₋₁₅alkyl, halo, NO₂, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²²,SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂,N(R²⁰)₂NR²⁰COR²² , NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰,CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²²,OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂, —CONR⁷R⁸,C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl,wherein the alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroarylsubstituents are optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of halo, alkyl, NO₂,heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²²,SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂,N(R²⁰)₂NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰,CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²²,OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂ and whereinthe optional substituted heteroaryl, aryl, and heterocyclyl substituentsare optionally substituted with halo, NO₂, alkyl, CF₃, amino, mono- ordi- alkylamino, alkyl or aryl or heteroaryl amide, NCOR²², NR²⁰SO₂R²²,COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R²⁰)₂, SR²⁰,S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰;

[0081] R⁵ and R⁶ are each individually selected from H, and C₁-C₁₅ alkylthat is optionally substituted with from 1 to 2 substituentsindependently selected from the group of halo, NO₂, heterocyclyl, aryl,heteroaryl, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂,SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂, N(R²⁰)₂NR²⁰COR²²,NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂,CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰,C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂ wherein each optional substitutedheteroaryl, aryl, and heterocyclyl substituent is optionally substitutedwith halo, NO₂, alkyl, CF₃, amino, monoalkylamino, dialkylamino,alkylamide, arylamide, heteroarylamide, NCOR²², NR²⁰SO₂R²², COR²⁰,CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R²⁰)₂, SR²⁰, S(O)R²²,SO₂R²², SO₂N(R²⁰)₂, CN, and OR²⁰;

[0082] R⁷ is selected from the group consisting of hydrogen, C₁₋₁₅alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl and heteroaryl,wherein the alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroarylsubstituents are optionally substituted with from 1 to 3 substituentsindependently selected from the group of halo, NO₂, heterocyclyl, aryl,heteroaryl, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂,SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂, N(R²⁰)₂NR²⁰COR²²,NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂,CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰,C(O)OCH₂OC(O)R²⁰ and OCON(R²⁰)₂ and wherein each optional substitutedheteroaryl, aryl and heterocyclyl substituent is optionally substitutedwith halo, NO₂, alkyl, CF₃, amino, mono- or di-alkylamino, alkyl or arylor heteroaryl amide, NCOR²², NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂,NR²⁰CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R²⁰)₂, SR²⁰, S(O)R²², SO₂R²²,SO₂N(R²⁰)₂, CN, and OR²⁰;

[0083] R⁸ is selected from the group consisting of hydrogen, C₁₋₁₅alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl,wherein the alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroarylsubstituents are optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of halo, NO₂,heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²²,SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂,N(R²⁰)₂NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰,CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²²,OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂ and whereineach optional substituted heteroaryl, aryl, and heterocyclyl substituentis optionally substituted with halo, NO₂, alkyl, CF₃, amino, mono- ordi-alkylamino, alkyl or aryl or heteroaryl amide, NCOR²², NR²⁰SO₂R²²,COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R²⁰)₂, SR²⁰,SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, and OR²⁰;

[0084] R²⁰ is selected from the group consisting of H, C₁₋₁₅ alkyl,C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl,wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroarylsubstituents are optionally substituted with from 1 to 3 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl;

[0085] R²² is selected from the group consisting of C₁₋₁₅ alkyl,_(C2-15) alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl,wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroarylsubstituents are optionally substituted with from 1 to 3 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl;and wherein R² and R⁴ are selected from the group consisting of H, C₁₋₆alkyl and aryl, wherein the alkyl and aryl substituents are optionallysubstituted with halo, CN, CF₃, OR²⁰ and N(R²⁰)₂ with the proviso thatwhen R² is not hydrogen then R⁴ is hydrogen, and when R⁴ is not hydrogenthen R² is hydrogen.

[0086] In an related group of compounds of this invention, R³ isselected from the group consisting of C₁₋₁₅ alkyl, halo, CF₃, CN, OR²⁰,SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, COR²⁰, CO₂R²⁰, —CONR⁷R⁸, aryl andheteroaryl wherein the alkyl, aryl and heteroaryl substituents areoptionally substituted with from 1 to 3 substituents independentlyselected from the group consisting of halo, aryl, heteroaryl, CF₃, CN,OR²⁰, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, COR²⁰, CO₂R²⁰ or CON(R²⁰)₂, andeach optional heteroaryl and aryl substituent is optionally substitutedwith halo, alkyl, CF₃ CN, and OR²⁰; R⁵ and R⁶ are independently selectedfrom the group of H and C₁-C₁₅ alkyl including one optional arylsubstituent and each optional aryl substituent that is optionallysubstituted with halo or CF₃; R⁷ is selected from the group consistingof C₁₋₁₅ alkyl, C₂₋₁₅ alkynyl, aryl, and heteroaryl, wherein the alkyl,alkynyl, aryl, and heteroaryl substituents are optionally substitutedwith from 1 to 3 substituents independently selected from the groupconsisting of halo, aryl, heteroaryl, CF₃, CN, OR²⁰, and each optionalheteroaryl and aryl substituent is optionally substituted with halo,alkyl, CF₃ CN, or OR²⁰; R⁸ is selected from the group consistingofhydrogen and C₁₋₁₅alkyl; R²⁰ is selected from the group consisting ofH, C₁₋₄ alkyl and aryl, wherein alkyl and aryl substituents areoptionally substituted with one alkyl substituent; and R²² is selectedfrom the group consisting of C₁₋₄ alkyl and aryl which are eachoptionally substituted with from 1 to 3 alkyl group.

[0087] In yet another related class of compounds, R¹ is CH₂OH; R³ isselected from the group consisting of CO₂R²⁰, —CONR⁷R⁸ and aryl wherethe aryl substituent is optionally substituted with from 1 to 2substituents independently selected from the group consisting of halo,C₁₋₆ alkyl, CF₃ and OR²⁰; R⁷is selected from the group consisting ofhydrogen, C₁₋₈ alkyl and aryl, where the alkyl and aryl substituents areoptionally substituted with one substituent selected from the groupconsisting of halo, aryl, CF₃, CN, OR²⁰ and wherein each optional arylsubstituent is optionally substituted with halo, alkyl, CF₃ CN, andOR²⁰; R⁸ is selected from the group consisting of hydrogen and C₁₋₈alkyl; and R²⁰ is selected from hydrogen and C₁₋₄ alkyl.

[0088] In a still another related class of compounds of this invention,R¹═CH₂OH; R³ is selected from the group consisting of CO₂R²⁰, —CONR⁷R⁸,and aryl that is optionally substituted with one substituent selectedfrom the group consisting of halo, C₁₋₃ alkyl and OR²⁰; R⁷ is selectedfrom of hydrogen, and C₁₋₃ alkyl; R⁸ is hydrogen; and R²⁰ is selectedfrom hydrogen and C₁₋₄ alkyl. In this preferred embodiment, R³ is mostpreferably selected from —CO₂Et and —CONHEt.

[0089] In yet another related class of compounds, R¹═—CONHEt, R³ isselected from the group consisting of CO₂R²⁰, —CONR⁷R⁸, and aryl in thataryl is optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of halo, C₁₋₃ alkyl,CF₃ or OR²⁰; R⁷is selected from the group consisting of hydrogen, andC₁₋₈ alkyl that is optionally substituted with one substituent selectedfrom the group consisting of halo, CF₃, CN or OR²⁰; R⁸ is selected fromthe group consisting of hydrogen and C₁₋₃ alkyl; and R²⁰ is selectedfrom the group consisting of hydrogen and C₁₋₄ alkyl. In this morepreferred embodiment, R⁸ is preferably hydrogen, R⁷ is preferablyselected from the group consisting of hydrogen, and C₁₋₃, and R²⁰ ispreferably selected from the group consisting of hydrogen and C₁₋₄alkyl.

[0090] Specific useful compounds are selected from ethyl1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylate,(4S,2R,3R,5R)-2-{6-amino-2-[4-(4-chlorophenyl)pyrazolyl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol, (4S,2R,3R,5R)-2-{6-amino-2-[4-(4-methoxyphenyl)pyrazol]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-{6-amino-2-[4-(4-methylphenyl)pyrazolyl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol,(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamide,1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylicacid,(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N,N-dimethylcarboxamide,(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-ethylcarboxamide,1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxamide,1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-(cyclopentylmethyl)carboxamide,(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-[(4-chlorophenyl)methyl]carboxamide, Ethyl2-[(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)carbonylamino]acetate,and mixtures thereof.

[0091] A second class of compounds that are potent and selectiveagonists for the A_(2A) adenosine receptor that are useful in themethods of this invention are 2-adenosine C-pyrazole compounds havingthe following formula:

[0092] wherein R¹ is —CH₂OH, and —C(═O)NR⁵R⁶;

[0093] R² is selected from the group consisting of hydrogen, C₁₋₁₅alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl,wherein the alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroarylsubstituents are optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of halo, NO₂,heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰ , N(R²⁰)₂, S(O)R²²,SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂,N(R²⁰)₂NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰,CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²²,OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂ and whereineach optional heteroaryl, aryl, and heterocyclyl substituent isoptionally substituted with halo, NO₂, alkyl, CF₃, amino, mono- ordi-alkylamino, alkyl or aryl or heteroaryl amide, NCOR²², NR²⁰SO₂R²²,COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰ CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R²⁰)₂, SR²⁰,S(O)R²², SO₂N(R²⁰)₂, CN, or OR²⁰;

[0094] R³, R⁴ are individually selected from the group consisting ofhydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl,and heteroaryl, halo, NO₂, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²²,SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂,N(R²⁰)₂NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰,CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²²,OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂ wherein thealkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl substituentsare optionally substituted with from 1 to 3 substituents individuallyselected from the group consisting of halo, NO₂, heterocyclyl, aryl,heteroaryl, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂,SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂, N(R²⁰)₂NR²⁰COR²²,NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂,CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰,C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂ and wherein each optional heteroaryl,aryl, and heterocyclyl substituent is optionally substituted with halo,NO₂, alkyl, CF₃, amino, mono- or di-alkylamino, alkyl or aryl orheteroaryl amide, NCOR²², NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂,NR²⁰CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R²⁰)₂, SR²⁰, S(O)R²², SO₂R²²,SO₂N(R²⁰)₂, CN, or OR²⁰;

[0095] R⁵ and R⁶ are each individually H, C1-15 alkyl with from 1 to 2substituents independently selected from the group consisting of halo,NO₂, heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂,S(O)R²², SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²²,SO₂NR²⁰CON(R²⁰)₂, N(R²⁰)₂NR²⁰COR²², NR²⁰ CO₂R²², NR²⁰CON(R²⁰)₂,NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²²,SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂and wherein each optional heteroaryl, aryl, and heterocyclyl substituentis optionally substituted with halo, NO₂, alkyl, CF₃, amino, mono- ordi-alkylamino, alkyl or aryl or heteroaryl amide, NCOR²², NR²⁰SO₂R²²,COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R²⁰)₂, SR²⁰,S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰;

[0096] R²⁰ is selected from the group consisting of H, C₁₋₁₅ alkyl,C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl,wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroarylsubstituents are optionally substituted with from 1 to 3 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl;and

[0097] R²² is a member selected from the group consisting of C₁₋₁₅alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl,wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroarylsubstituents are optionally substituted with from 1 to 3 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃, and heteroaryl wherein,when R¹═CH₂OH, R³ is H, R⁴ is H, the pyrazole ring is attached throughC⁴, and R² is not H.

[0098] When the compound is selected has one of the following formulas:

[0099] then it is preferred that R¹ is —CH₂OH; R² is selected from thegroup consisting of hydrogen, C₁₋₈ alkyl wherein the alkyl is optionallysubstituted with one substituent independently selected from the groupconsisting of aryl, CF₃, CN, and wherein each optional aryl substituentis optionally substituted with halo, alkyl, CF₃ or CN; and R³ and R⁴ areeach independently selected from the group consisting of hydrogen,methyl and more preferably, R³ and R⁴ are each hydrogen.

[0100] When the compound of this invention has the following formulas:

[0101] then it is preferred that R¹ is —CH₂OH; R² is selected from thegroup consisting of hydrogen, and C₁₋₆ alkyl optionally substituted byphenyl. More preferably, R² is selected from benzyl and pentyl; R³ isselected from the group consisting of hydrogen, C₁₋₆ alkyl, aryl,wherein the alkyl, and aryl substituents are optionally substituted withfrom 1 to 2 substituents independently selected from the groupconsisting of halo, aryl, CF₃, CN, and wherein each optional arylsubstituent is optionally substituted with halo, alkyl, CF₃ or CN; andR⁴ is selected from the group consisting of hydrogen and C₁₋₆ alkyl, andmore preferably, R⁴ is selected from hydrogen and methyl.

[0102] A more specific class of compounds is selected from the groupconsisting of(4S,2R,3R,5R)-2-{6-amino-2-[1-benzylpyrazol-4-yl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-[6-amino-2-(1-pentylpyrazol-4-yl)purin-9yl]-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-[6-amino-2-(1-methylpyrazol-4-yl)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-{6-amino-2-[1-(methylethyl)pyrazol-4-yl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-{6-amino-2-[1-(3-phenylpropyl)pyrazol-4-yl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-{6-amino-2-[1-(4-t-butylbenzyl)pyrazol-4-yl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-(6-amino-2-pyrazol-4-ylpurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-{6-amino-2-[1-pent-4-enylpyrazol-4-yl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-{6-amino-2-[1-decylpyrazol-4-yl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-}6-amino-2-[1-(cyclohexylmethyl)pyrazol-4-yl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-{6-amino-2-[1-(2-phenylethyl)pyrazol-4-yl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-{6-amino-2-[1-(3-cyclohexylproply)pyrazol-4-yl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol,(4S,2R,3R,5R)-2-{6-amino-2-[1-(2-cyclohexylethyl)pyrazol-4-yl]purin-9-yl}-5-(hyudroxymethyl)oxolane-3,4-diol,and combinations thereof.

[0103] A very useful and potent and selective agonists for the A_(2A)adenosine receptor is CVT-3146 or(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylcarboxamidewhich has the formula:

[0104] Another preferred compound that is useful as a selectiveA_(2A)-adenosine receptor agonist with a short duration of action is acompound of the formula:

[0105] CVT-3033 is particularly useful as an adjuvant in cardiologicalimaging.

[0106] The first and second classes of compounds identified above aredescribed in more detail in U.S. Pat. Nos. 6,403,567 and 6,214,807, thespecification of each of which is incorporated herein by reference.

[0107] The following definitions apply to terms as used herein.

[0108] “Halo” or “Halogen”—alone or in combination means all halogens,that is, chloro (Cl), fluoro (F), bromo (Br), iodo (I).

[0109] “Hydroxyl” refers to the group —OH.

[0110] “Thiol” or “mercapto” refers to the group —SH.

[0111] “Alkyl”—alone or in combination means an alkane-derived radicalcontaining from 1 to 20, preferably 1 to 15, carbon atoms (unlessspecifically defined). It is a straight chain alkyl, branched alkyl orcycloalkyl. Preferably, straight or branched alkyl groups containingfrom 1-15, more preferably 1 to 8, even more preferably 1-6, yet morepreferably 1-4 and most preferably 1-2, carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, t-butyl and the like. The term “loweralkyl” is used herein to describe the straight chain alkyl groupsdescribed immediately above. Preferably, cycloalkyl groups aremonocyclic, bicyclic or tricyclic ring systems of 3-8, more preferably3-6, ring members per ring, such as cyclopropyl, cyclopentyl,cyclobexyl, adamantyl and the like. Alkyl also includes a straight chainor branched alkyl group that contains or is interrupted by a cycloalkylportion. The straight chain or branched alkyl group is attached at anyavailable point to produce a stable compound. Examples of this include,but are not limited to, 4-(isopropyl)-cyclohexylethyl or2-methyl-cyclopropylpentyl. A substituted alkyl is a straight chainalkyl, branched alkyl, or cycloalkyl group defined previously,independently substituted with 1 to 3 groups or substituents of halo,hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy,aryloxy, heteroaryloxy, amino optionally mono- or di-substituted withalkyl, aryl or heteroaryl groups, amidino, urea optionally substitutedwith alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyloptionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroarylgroups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike.

[0112] “Alkenyl”—alone or in combination means a straight, branched, orcyclic hydrocarbon containing 2-20, preferably 2-17, more preferably2-10, even more preferably 2-8, most preferably 2-4, carbon atoms and atleast one, preferably 1-3, more preferably 1-2, most preferably one,carbon to carbon double bond. In the case of a cycloalkyl group,conjugation of more than one carbon to carbon double bond is not such asto confer aromaticity to the ring. Carbon to carbon double bonds may beeither contained within a cycloalkyl portion, with the exception ofcyclopropyl, or within a straight chain or branched portion. Examples ofalkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,cyclohexenyl, cyclohexenylalkyl and the like. A substituted alkenyl isthe straight chain alkenyl, branched alkenyl or cycloalkenyl groupdefined previously, independently substituted with 1 to 3 groups orsubstituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono-or di-substituted with alkyl, aryl or heteroaryl groups, amidino, ureaoptionally substituted with alkyl, aryl, heteroaryl or heterocyclylgroups, aminosulfonyl optionally N-mono- or N,N-di-substituted withalkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, or the like attached at any available point toproduce a stable compound. “Alkynyl”—alone or in combination means astraight or branched hydrocarbon containing 2-20, preferably 2-17, morepreferably 2-10, even more preferably 2-8, most preferably 2-4, carbonatoms containing at least one, preferably one, carbon to carbon triplebond. Examples of alkynyl groups include ethynyl, propynyl, butynyl andthe like. A substituted alkynyl refers to the straight chain alkynyl orbranched alkenyl defined previously, independently substituted with 1 to3 groups or substituents of halo, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, aminooptionally mono- or di-substituted with alkyl, aryl or heteroarylgroups, amidino, urea optionally substituted with alkyl, aryl,heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- orN,N-di-substituted with alkyl, aryl or heteroaryl groups,alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike attached at any available point to produce a stable compound.

[0113] “Alkyl alkenyl” refers to a group —R—CR′═CR′″R″″, where R islower alkyl, or substituted lower alkyl, R′, R′″, R″″ may independentlybe hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl,substituted aryl, hetaryl, or substituted hetaryl as defined below.

[0114] “Alkyl alkynyl” refers to a groups —RC□OCR′ where R is loweralkyl or substituted lower alkyl, R′ is hydrogen, lower alkyl,substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl, orsubstituted hetaryl as defined below.

[0115] “Alkoxy” denotes the group —OR, where R is lower alkyl,substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl,substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, or substitutedcycloheteroalkyl as defined.

[0116] “Alkylthio” denotes the group —SR, —S(O)_(n=1-2)—R, where R islower alkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl orsubstituted aralkyl as defined herein.

[0117] “Acyl” denotes groups —C(O)R, where R is hydrogen, lower alkylsubstituted lower alkyl, aryl, substituted aryl and the like as definedherein.

[0118] “Aryloxy” denotes groups —OAr, where Ar is an aryl, substitutedaryl, heteroaryl, or substituted heteroaryl group as defined herein.

[0119] “Amino” denotes the group NRR′, where R and R′ may independentlyby hydrogen, lower alkyl, substituted lower alkyl, aryl, substitutedaryl, hetaryl, or substituted hetaryl as defined herein or acyl.

[0120] “Amido” denotes the group —C(O)NRR′, where R and R′ mayindependently by hydrogen, lower alkyl, substituted lower alkyl, aryl,substituted aryl, hetaryl, substituted hetaryl as defined herein.

[0121] “Carboxyl” denotes the group —C(O)OR, where R is hydrogen, loweralkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, andsubstituted hetaryl as defined herein.

[0122] “Aryl”—alone or in combination means phenyl or naphthyloptionally carbocyclic fused with a cycloalkyl of preferably 5-7, morepreferably 5-6, ring members and/or optionally substituted with 1 to 3groups or substituents of halo, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, aminooptionally mono- or di-substituted with alkyl, aryl or heteroarylgroups, amidino, urea optionally substituted with alkyl, aryl,heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- orN,N-di-substituted with alkyl, aryl or heteroaryl groups,alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike.

[0123] “Substituted aryl” refers to aryl optionally substituted with oneor more functional groups, e.g., halogen, lower alkyl, lower alkoxy,alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy,heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

[0124] “Heterocycle” refers to a saturated, unsaturated, or aromaticcarbocyclic group having a single ring (e.g., morpholino, pyridyl orfuryl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl,quinolinyl, indolizinyl or benzo[b]thienyl) and having at least onehetero atom, such as N, O or S, within the ring, which can optionally beunsubstituted or substituted with, e.g., halogen, lower alkyl, loweralkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl,aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

[0125] “Heteroaryl”—alone or in combination means a monocyclic aromaticring structure containing 5 or 6 ring atoms, or a bicyclic aromaticgroup having 8 to 10 atoms, containing one or more, preferably 1-4, morepreferably 1-3, even more preferably 1-2, heteroatoms independentlyselected from the group O, S, and N, and optionally substituted with 1to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, aminooptionally mono- or di-substituted with alkyl, aryl or heteroarylgroups, amidino, urea optionally substituted with alkyl, aryl,heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- orN,N-di-substituted with alkyl, aryl or heteroaryl groups,alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike. Heteroaryl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon ornitrogen atom is the point of attachment of the heteroaryl ringstructure such that a stable aromatic ring is retained. Examples ofheteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl,purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl,thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl and thelike. A substituted heteroaryl contains a substituent attached at anavailable carbon or nitrogen to produce a stable compound.

[0126] “Heterocyclyl”—alone or in combination means a non-aromaticcycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbonatoms in the ring are replaced by heteroatoms of O, S or N, and areoptionally benzo fused or fused heteroaryl of 5-6 ring members and/orare optionally substituted as in the case of cycloalkyl. Heterocycyl isalso intended to include oxidized S or N, such as sulfinyl, sulfonyl andN-oxide of a tertiary ring nitrogen. The point of attachment is at acarbon or nitrogen atom. Examples of heterocyclyl groups aretetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl,piperazinyl, dihydrobenzofuryl, dihydroindolyl, and the like. Asubstituted hetercyclyl contains a substituent nitrogen attached at anavailable carbon or nitrogen to produce a stable compound.

[0127] “Substituted heteroaryl” refers to a heterocycle optionally monoor poly substituted with one or more functional groups, e.g., halogen,lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl,hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0128] “Aralkyl” refers to the group —R—Ar where Ar is an aryl group andR is lower alkyl or substituted lower alkyl group. Aryl groups canoptionally be unsubstituted or substituted with, e.g., halogen, loweralkyl, alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl,aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0129] “Heteroalkyl” refers to the group —R-Het where Het is aheterocycle group and R is a lower alkyl group. Heteroalkyl groups canoptionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, aryl,aryloxy, heterocycle, substituted heterocycle, hetaryl, substitutedhetaryl, nitro, cyano, thiol, sulfamido and the like.

[0130] “Heteroarylalkyl” refers to the group —R-HetAr where HetAr is anheteroaryl group and R lower alkyl or substituted lower alkyl.Heteroarylalkyl groups can optionally be unsubstituted or substitutedwith, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy,alkylthio, acetylene, aryl, aryloxy, heterocycle, substitutedheterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

[0131] “Cycloalkyl” refers to a divalent cyclic or polycyclic alkylgroup containing 3 to 15 carbon atoms.

[0132] “Substituted cycloalkyl” refers to a cycloalkyl group comprisingone or more substituents with, e.g., halogen, lower alkyl, substitutedlower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle,substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano,thiol, sulfamido and the like.

[0133] “Cycloheteroalkyl” refers to a cycloalkyl group wherein one ormore of the ring carbon atoms is replaced with a heteroatom (e.g., N, O,S or P).

[0134] Substituted cycloheteroalkyl” refers to a cycloheteroalkyl groupas herein defined which contains one or more substituents, such ashalogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido,carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle,hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and thelike.

[0135] “Alkyl cycloalkyl” denotes the group —R-cycloalkyl wherecycloalkyl is a cycloalkyl group and R is a lower alkyl or substitutedlower alkyl. Cycloalkyl groups can optionally be unsubstituted orsubstituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio,acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle,substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano,thiol, sulfamido and the like.

[0136] “Alkyl cycloheteroalkyl” denotes the group —R-cycloheteroalkylwhere R is a lower alkyl or substituted lower alkyl. Cycloheteroalkylgroups can optionally be unsubstituted or substituted with e.g. halogen,lower alkyl, lower alkoxy, alkylthio, amino, amido, carboxyl, acetylene,hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0137] The first class of compounds identified above can be prepared asoutlined in Schemes 1-4.

[0138] Compounds having the general formula IV can be prepared as shownin Scheme 1.

[0139] Compound I can be prepared by reacting compound 1 withappropriately substituted 1,3-dicarbonyl in a mixture of AcOH and MeOHat 80° C. (Holzer et al., J. Heterocycl. Chem. (1993) 30, 865). CompoundII, which can be obtained by reacting compound I with2,2-dimethoxypropane in the presence of an acid, can be oxidized to thecarboxylic acid III, based on structurally similar compounds usingpotassium permanganate or pyridinium chlorochromate (M. Hudlicky, (1990)Oxidations in Organic Chemistry, ACS Monographs, American ChemicalSociety, Washington D.C.). Reaction of a primary or secondary aminehaving the formula HNR⁶R⁷, and compound III using DCC (M. Fujino et al.,Chem. Pharm. Bull. (1974), 22, 1857), PyBOP (J. Martinez et al., J. Med.Chem. (1988) 28, 1874) or PyBrop (J. Caste et al. Tetrahedron, (1991),32, 1967) coupling conditions can afford compound IV.

[0140] Compound V can be prepared as shown in Scheme 2. The Tri TBDMSderivative 4 can be obtained by treating compound 2 with TBDMSCI andimidazole in DMF followed by hydrolysis of the ethyl ester using NaOH.Reaction of a primary or secondary amine with the formula HNR⁶R⁷, andcompound 4 using DCC (M. Fujino et al., Chem. Pharm. Bull. (1974), 22,1857), PyBOP (J. Martinez et al., J. Med. Chem. (1988) 28, 1874) orPyBrop (J. Caste et al. Tetrahedron, (1991), 32, 1967) couplingconditions can afford compound V.

[0141] A specific synthesis of Compound 11 is illustrated in Scheme 3.Commercially available guanosine 5 was converted to the triacetate 6 aspreviously described (M. J. Robins and B. Uznanski, Can. J. Chem.(1981), 59, 2601-2607). Compound 7, prepared by following the literatureprocedure of Cerster et al. (J. F. Cerster, A. F. Lewis, and R. K.Robins, Org. Synthesis, 242-243), was converted to compound 9 in twosteps as previously described (V. Nair et al., J. Org. Chem., (1988),53, 3051-3057). Compound 1 was obtained by reacting hydrazine hydratewith compound 9 in ethanol at 80° C. Condensation of compound 1 withethoxycarbonylmalondialdehyde in a mixture of AcOH and MeOH at 80° C.produced compound 10. Heating compound 10 in excess methylamine affordedcompound 11.

[0142] The synthesis of 1,3-dialdehyde VII is described in Scheme 4.Reaction of 3,3-diethoxypropionate or 3,3-diethoxypropionitrile or1,1-diethoxy-2-nitroethane VI (R₃═CO₂R, CN or NO₂) with ethyl or methylformate in the presence of NaH can afford the dialdehyde VII (Y.Yamamoto et al., J. Org. Chem. (1989) 54, 4734).

[0143] The second class of compound described above may be prepared byas outlined in

[0144] schemes 1-5. Compounds having the general formula II: wereprepared by the palladium mediated coupling of compound 1 withhalo-pyrazoles represented by the formula VIII (scheme 4) in thepresence or absence of copper salts (K. Kato et. al. J. Org. Chem. 1997,62, 6833-6841; Palladium Reagents and Catalysts-Innovations in OrganicSynthesis, Tsuji, John Wiley and Sons, 1995) followed by de-protectionwith either TBAF or NH₄F (Markiewicz et. al Tetrahedron Lett.(1988), 29,1561). The preparation of compound 1 has been previously described (K.Kato et. al. J. Org. Chem. 1997, 62, 6833-684 1) and is outlined inscheme 5.

[0145] Compounds with general formula VI can be prepared as shown inScheme 2. Compound III, which can be obtained by reacting II with2,2-dimethoxypropane in presence of an

[0146] acid, can be oxidized to the carboxylic acid IV, based onstructurally similar compounds, using potassium permanganate orpyridinium chlorochromate etc. ( Jones et.al., J. Am. Chem. Soc.(1949),71, 3994.; Hudlicky, Oxidations in organic chemistry, American ChemicalSociety, Washington D.C., 1990) to compound IV. Reaction of primary orsecondary amine of the formula NHR⁵R⁶, and compound IV using DCC (Fujinoet.al., Chem. Pharm. Bull. (1974), 22, 1857), PyBOP (J. Martinez et.al., J. Med. Chem. (1988), 28, 1967) or PyBrop (J. Caste et.al.Tetrahedron, (1991), 32, 1967) coupling conditions can afford compoundV. Deprotection of compound V can be performed by heating with 80% aq.acetic acid (T. W. Green and P. G. M.

[0147] Wuts, (1991), Protective Groups in Organic Synthesis, A,Wiley-Interscience publication) or with anhydrous HCl (4N) to obtaincompound of the general formula VI.

[0148] Alternatively, compounds with the general formula II can also beprepared by Suzuki type coupling as shown in scheme 3. 2-Iodoadenosine 6can be prepared in four steps from guanosine 2 following literatureprocedures (M. J. Robins et.al. Can. J. Chem. (1981), 59, 2601-2607; J.F. Cerster et.al. Org. Synthesis, - - - 242-243; V. Nair at. al., J.Org. Chem., (1988), 53, 3051-3057). Palladium mediated Suzuki couplingof 6 with appropriately substituted pyrazole-boronic acids XVII inpresence of a base can provide final compounds with general formula II(A. Suzuki, Acc. Chem. Res) (1982), 15, 178). If necessary, 2′, 3′, 5′hydroxyls on 6 can be protected as TBDMS ethers prior to Suzukicoupling.

[0149] Compounds with the general formula VIII can be eithercommercially available or prepared following the steps shown in scheme4.

[0150] Condensation of 1,3-diketo compounds of the formula IX withhydrazine in an appropriate solvent can give pyrazoles with the generalformula X (R. H. Wiley et. al. Org. Synthsis, Coll. Vol IV (1963), 351.These pyrazoles can be N-alkylated with various alkyl halides to givecompounds of the formula XI which on iodination give 4-iodo derivativeswith the general formula VIII (R. Huttel et.al. Justus Liebigs Ann.Chem.(1955), 593, 200).

[0151] 5-iodopyrazoles with the general formula XV can be preparedfollowing the steps outlined in the scheme 5.

[0152] Condensation of 1,3-diketo compounds of the formula XII withhydrazine in an appropriate solvent can give pyrazoles with the generalformula XIII. These pyrazoles can be N-alkylated with various alkylhalides to give compounds of the formula XIV. Abstraction of 5-H with astrong base followed by quenching with iodine can provide 5-iododerivatives with general formula XV (F. Effenberger et. al. J. Org.Chem. (1984), 49, 4687).

[0153] 4- or 5-iodopyrazoles can be transformed into correspondingboronic acids as shown in the scheme 6. Transmetallation with n-buLifollowed by treatment with trimethylborate can

[0154] give compounds with the general formula XVI which on hydrolysiscan provide boronic acids with the general formula XVII (F. C. Fischeret.al. RECUEIL (1965), 84, 439).

[0155] 2-Stannyladenosine 1 was prepared in three steps from thecommercially available 6-chloropurine riboside following literatureprocedure (K. Kato et.al., J. Org. Chem. (1997), 62, 6833-6841). TriTBDMS derivative was obtained by treating 8 with TBDMSCI and imidazolein DMF. Lithiation with LTMP followed by quenching with tri n-butyltinchloride gave exclusively 2-stannyl derivative 10. Ammonolysis in2-propanol gave 2-stannyladenosine 1. Stille coupling of 1 with1-benzyl-4-iodopyrazole in presence of Pd(PPh3)4 and Cul resulted in 11(K. Kato et.al., J. Org. Chem. (1997), 62, 6833-6841). Deprotection ofsilyl groups on 2′, 3′ and 5′

[0156] hydroxyls with 0.5 M ammonium fluoride in methanol gave 12 ingood yield (Scheme 7). The methods used to prepare the compounds of thisinvention are not limited to those described above. Additional methodscan be found in the following sources and are included by reference (J.March, Advanced Organic Chemistry; Reaction Mechanisms and Studies(1992), A Wiley Interscience Publications; and J. Tsuji, Palladiumreagents and catalysts-Innovations in organic synthesis, John Wiley andSons, 1995).

[0157] If the final compound of this invention contains a basic group,an acid addition salt may be prepared. Acid addition salts of thecompounds are prepared in a standard manner in a suitable solvent fromthe parent compound and an excess of acid, such as hydrochloric,hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic, or methanesulfonic. The hydrochloric salt form is especially useful. If the finalcompound contains an acidic group, cationic salts may be prepared.Typically the parent compound is treated with an excess of an alkalinereagent, such as hydroxide, carbonate or alkoxide, containing theappropriate cation. Cations such as Na⁺, K⁺, Ca⁺² and NH₄ ⁺ are examplesof cations present in pharmaceutically acceptable salts. Certain of thecompounds form inner salts or zwittcrions which may also be acceptable.

EXAMPLE 1

[0158] BACKGROUND: CVT-3146 (CVT), with an initial half-life of 3minutes with a rapid onset and offset of action, is >100-fold morepotent than adenosine (Ado) in increasing coronary blood flow velocity(CBFv) in awake dogs. The purpose of this open label study was todetermine the magnitude and duration of effect of CVT-3146 (10-500 μg)on CBFv in humans.

[0159] METHODS: Patients undergoing a clinically indicated coronarycatheterization with no more than a 70% stenosis in any coronary arteryand no more than a 50% stenosis of the study vessel had CBFv determinedby Doppler flow wire. Study subject were selected after measuringbaseline and peak CBFv after an intracoronary (IC) injection of 18 μg ofAdo. Twenty-three patients, who were identified as meeting the studycriteria of having a peak to baseline CBFv ratio of ≧2.5 in response toAdenosine, received a rapid (≦10 sec) peripheral IV bolus of CVT-3146;Doppler signals were stable and interpretable over the time-course ofthe increase in CBFv in 17 patients.

[0160] RESULTS CVT-3146 caused a rapid increase in CBFv that was nearpeak by 30 to 40 seconds post onset of bolus. CVT-3146 at doses of 100μg (n=3), 300 μg (n=4), and 500 μg (n=2) induced a peak to baselineratio of 3.2±0.6 (mean±SD), similar to that obtained by IC Ado(3.2±0.5). The duration of CBFv augmentation (≧2-fold increase in CBFv)was dose dependent; at 300 μg the duration was 4.0±4.9 minutes and at500 μg was 6.9±7.6 minutes. At 500 μg (n=3) the maximal increase inheart rate (HR) was 18.7±4.0 and the maximal decrease in systolic bloodpressure (BP) was 8.7±7.6. Adverse events (AEs) were infrequent andincluded nausea, flushing, and headache; these were mild andself-limited. No AEs were noted in the 3 patients receiving the 500 μgdose.

[0161] CONCLUSION: In humans peak CBFv following CVT-3146 (IV bolus) iscomparable to CBFv following IC Ado without major changes in either HRor BP. This agent's magnitude and duration of effect, adverse eventprofile and bolus administration make CVT-3146 a useful pharmacologicalstress agent for myocardial perfusion imaging.

EXAMPLE 2

[0162] This example is a study performed to determine the range ofdosages over which the selective A_(2A) receptor agonist, CVT-3146 canbe administered and be effective as a coronary vasodilator.

[0163] The study included patients undergoing a clinically indicatedcoronary catheterization with no more than a 70% stenosis in anycoronary artery and no more than a 50% stenosis of the study vessel hadCBFv determined by Doppler flow wire. Study subject were selected aftermeasuring baseline and peak CBFv after an intracoronary (IC) injectionof 18 μg of Ado. 36 subjects were identified as meeting the studycriteria of having a peak to baseline CBFv ration of ≧2.5 in response toAdenosine,

[0164] CVT-3146 was administered to the study subjects by IV bolus inless that 10 seconds in amounts ranging from 10 μg to 500 μg.

[0165] The effectiveness of both compounds was measured by monitoringcoronary flow velocity. Other coronary parameters that were monitoredincluded heart rate and blood pressure. These parameters were measuredin order to evaluate the time to peak dose response, the magnitude ofthe dose response and the duration of the dose response. Adverse eventswere also monitored. Coronary blood flow velocity was measured at theleft anterior descending coronary artery (LAD) or left circumflexcoronary artery (LCx). The velocity measurements were taken by followingstandard heart catheterization techniques and inserting a 0.014 inchDoppler-tipped Flowire into the LAD or LCx vessel and thereaftermonitoring blood flow velocity. In addition, hemodynamic andelectrocardiographic measurements were recorded continuously.

[0166] Overall, 36 human subjects (n=36) were evaluated. Of the 36, 18were female and 18 were male. Their mean age was 53.4 and they rangedfrom 24-72 years in age. Of the 36 subjects evaluated, the LAD vessel of31 subjects was monitored, and the LCx vessel of 5 subjects wasmonitored. The following doses (μg) of CVT-3146 were given to thesubjects in a single iv bolus: 10 (n=4); 30 (n=6); 100 (n=4); 300 (n=7);400 (n=9); 500 (n=6).

[0167] The study results are reported in FIGS. 1-6. The plot of FIG. 1shows that CVT-3146 increases peak flow velocity in amounts as low as 10μg and reaches plateau peak velocity upon administration of less thanabout 100 μg of CVT-3146. Other test results and conclusions include:

[0168] The peak flow was reached by about 30 seconds with all doses;

[0169] At does above about 100 μg, peak effects were equivalent to 18 μgadenosine administered IC;

[0170] CVT-3146 was generally well tolerated with adverse events beingreported in The table attached as FIG. 7;

[0171] At 400 μg:

[0172] Coronary blood flow velocity ≧2.5-fold above baseline wasmaintained for 2.8 minutes.

[0173] Maximum increase in heart rate (18±8 bpm) occurs about 1 minuteafter dosing.

[0174] Maximum decrease in systolic BP (20±8 mmHg) occurs about 1 minuteafter dosing.

[0175] Maximum decrease in diastolic BP (10±5 mmHg) occurs about 1minute after dosing.

Example 3

[0176] This Example is a study performed to evaluate (1) the maximumtolerated dose of CVT-3146 and (2) the pharmacokinetic profile ofCVT-3146 in healthy volunteers, after a single IV bolus dose.

[0177] Methods

[0178] The study was performed using thirty-six healthy, non-smokingmale subjects between the ages of 18 and 59 and within 15% of ideal bodyweight.

[0179] Study design

[0180] The study was performed in phase 1, single center, double-blind,randomized, placebo-controlled, crossover, ascending dose study.Randomization was to CVT-3146 or placebo, in both supine and standingpositions.

[0181] CVT-3146 was administered as an IV bolus (20 seconds) inascending doses of 0.1, 0.3, 1.3, 10, 20 and 30 μg/kg.

[0182] Subjects received either CVT-3146 of placebo on Day 1 supine,then crossover treatment on Day 2 supine. On Day 3, subjects receivedCVT-3146 or placebo standing, then crossover treatment on Day 4standing.

[0183] Assessments

[0184] Patient safety was monitored by ECG, laboratory assessments, andcollection of vital signs and adverse events.

[0185] Pharmacokinetics:

[0186] Plasma samples were drawn during supine phase (Days 1 and 2) at0, 1, 2, 3, 4, 5, 7, 10, 15,20, 30,45 minutes after dosing and at 1,1.5., 2, 4, 6, 8, 12 and 24 hours after dosing. Urine was collected for24 hours for CVT-3146 excretion.

[0187] Pharmacodynamics:

[0188] The study evaluated the relationship of changes in heart rate todose in both standing and supine positions and plasma concentration inthe supine position.

[0189] Some of the study results are reported in FIGS. 8-14.

[0190] Results

[0191] Safety

[0192] In general, adverse events reflected the pharmacologic effect ofCVT-3146 and were related to vasodilation or an increase in heart rate(HR). Overall, adverse events were short-lived and mild to moderate inseverity. There were no serious adverse events. Three events wereassessed as severe in intensity. (Table 1). TABLE 1 Adverse Eventslabeled as severe in intensity Number of Subjects with AE 20 μg/kg 30μg/kg Event Standing Supine No subjects per group 4 4 Palpitation 0 2Dizziness 1 0 Syncope 1 0

[0193] A three-compartment open model was fit to the data using observedTmax (1-4 minutes) as the duration of a zero-order infusion. Reliableparameter estimates were obtained for dose of 1-30 μg/kg. Parameters aresummarized in the following (Table 2): TABLE 2 Mean (SD) CVT-3146Pharmacokinetic Parameters Estimated Using a Three-Compartment ModelDose (μg/kg) 1 3 10 20 30 Total N 3 4 4 8 3 22 CL (mL/min) 737 668 841743 1021 768 (106) (167) (120) (123) (92.7) (168) Vc (L) 9.84 (4.12)13.7 (6.06) 17.9 (6.11) 12.5 15.7 13.8 (5.83) (4.59) (5.67) Vss (L) 69.0(28.2) 90.0 (29.6) 101 (11.3) 75.2 89.6 75.5 (10.6) (10.9) (24.4) αHaif-life 2.14 3.11 4.15 4.69 3.00 3.73 (min) (1.38) (2.14) (2.75)(4.01) (1.05) (2.88) β Half-life 8.93 17.2 50.2 32.6 14.0 27.2 (min)(4.10) (11.4) (52.1) (32.4) (4.98) (31.0) γ Half-life 99.0 130 132 11799.4 86.4 (min) (28.6) (23.1) (20.5) (36.0) (8.10) (57.5) K21 (l/min)0.246 0.203 0.187 0.387 0.0948 0.258 (0.255) (0.272) (0.305) (0.615)(0.0443) (0.410) K31 (l/min) 0.01808 0.0152 0.0108 0.0141 0.0148 0.0143(0.00548) (0.00490) (0.00592) (0.00728) (0.000900) (0.00580)

[0194] Results

[0195] CVT-3146 was well-tolerated, with AE's mainly representing itspharmacological effects as an adenosine A_(2A) receptor agonist.

[0196] Mean tolerable dose for CVT-3146 was 10 μg/kg standing and 20μg/kg supine.

[0197] CVT-3146 does not require weight-adjusted dosing.

[0198] There was no time lag between plasma concentration changes andchanges in heart rate.

[0199] The relationship between HR increase and dose or concentrationwas adequately described with a sigmoidal Emax model.

Example 4

[0200] CVT-3146 is a novel selective A_(2A) adenosine receptor agonistbeing developed as a pharmacologic stressor for radionuclide myocardialperfusion imaging. Previously it has been shown that CVT-3146 causescoronary vasodilation without significantly affecting either totalperipheral resistance or renal blood flow in awake dogs. The goal ofthis study was to determine the differential effects of CVT-3146 onblood flow velocity in various vascular beds.

[0201] The effect of CVT-3146 was studied on the blood flow velocity inleft circumflex coronary artery (LCX), brain arterial vasculature (BA),forelimb artery (FA) and pulmonary artery (PA) of comparable diameter inthe anesthetized dog. CVT3146 (1.0 μg/kg) was administered as anintravenous bolus, transiently enhanced blood flow which was sitespecific. The effects of CVT-3146 were quantified as the average peakblood flow velocity (APV) using intravascular Doppler transducer tippedcatheter. Heart rate (HR) and systemic arterial blood pressure (BP) werealso monitored.

[0202] APV increased 3.1±0.2, 1.4±0.1, 1.2±0.1, and 1.1±0.01 fold in theLCX, BA, FA and PA, respectively manifesting a site-potency rank orderof LCX>>BA>FA>PA (FIG. 16). The effect of CVT-3146 on blood flowvelocity was short lasting; reaching a peak in less than 30 sec anddissipating in less than ten minutes. Increased blood flow velocity wasassociated with a small transient increase in HR (16 bpm) and decreasein BP (12 mmHg). In conclusion, this study demonstrated that CVT-3146 isa potent, short lasting vasodilator that is highly selective for thecoronary vasculature.

Example 5

[0203] The present study was carried out to determine whether CVT-3146,a selective A_(2A) adenosine receptor agonist, causessympathoexcitation.

[0204] CVT (0.31 μg/kg-50 μg/kg) was given as a rapid i.v. bolus toawake rats and heart rate (HR) and blood pressure (BP) were monitored.CVT-3146 caused an increase in BP and systolic pressure (SP) at lowerdoses while at higher doses there was a decrease in BP and SP. CVT-3146caused a dose-dependent increase in HR (FIG. 17). The increase in HR wasevident at the lowest dose of CVT at which there was no appreciabledecrease in BP. ZM241385 (30 μg/kg , N=5), an A_(2A) receptorantagonist, attenuated the decrease in BP (CVT-3146: 14±3%, ZM: 1±1%)and the increase in HR (CVT: 27±3%, ZM: 18±3%) caused by CVT-3146.Pretreatment with metoprolol (MET, 1 mg/kg, n=5), a beta-blocker,attenuated the increase in HR (CVT: 27±3%, MET: 15±2%), but had noeffect on hypotension caused by CVT-3146. In the presence ofhexamethonium (HEX, 10 mg/kg, n=5), a ganglionic blocker, thetachycardia was prevented (CVT: 27±3%, HEX: −1±2%), but BP was furtherreduced (CVT: −11±2%, HEX: −49±5%). CVT-3146 (10 μg/kg, n=6) alsosignificantly (p<0.05) increased plasma norepinephrine (control: 146±11,CVT-3146 269±22 ng/ml) and epinephrine (control:25:f:5, CVT:I00:f:20ng/ml) levels. The separation of HR and BP effects by dose, time andpharmacological interventions provides evidence that tachycardia causedby CVT-3146 is independent of the decrease in BP, suggesting thatCVT-3146, via activation of A_(2A) receptors may cause a directstimulation of the sympathetic nervous system.

Example 6

[0205] Pharmacologic stress SPECT myocardial perfusion imaging (MPI)with adenosine (A) is a well-accepted technique, with excellentdiagnostic and prognostic value and proven I 0 safety. However, sideeffects are common and AV nodal block and severe flushing are poorlytolerated. Agents such as CVT-3146 selectively act upon the A2Aadenosine receptor and avoid stimulation of other receptor subtypeswhich may prevent such adverse reactions.

[0206] To determine the ability of CVT-3146 to produce coronaryhyperemia and accurately detect CAD, 35 subjects (26 men, 9 women; 67±10years) underwent both A and CVT-3146 stress/rest MPI, with 10.0±9.1 daysbetween studies. Prior MI was noted in 12 patients, and many had priorrevascularization [CABG (n=19),PCI (n=22)]. CVT-3146 [400 mcg (n=18),500 mcg (n=17)] was administered as an IV bolus immediately followed bya saline flush, and then a Tc-99m radiopharmaceutical [sestamibi (n=34),tetrofosmin (n=1)]. SPECT images were uniformly processed, intermixedwith control studies (normal and fixed-only defects), and interpreted bythree observers in a blinded fashion using a 17-segment model.Quantitative analysis was also performed using 4D MSPECT. In addition tothree separate readings, a consensus interpretation was performed andthen a direct, same-screen comparison of A and CVT-3146 imagesundertaken to determine relative differences, using 5 regions per study.

[0207] The summed scores following stress were similar, both with visual(A=13.9±1.5, CVT-3146=13.2±1.3; p=n.s.) and quantitative methods ofanalysis (A=13.7±1.5, CVT-3146=13.6±1.6; p=n.s.). Similarly, comparisonsbetween the summed rest and summed difference scores were identical. Thedirect comparison also revealed no differences in ischemia detection,with a regional concordance for ischemia extent and severity of 86.3%and 83.4%, respectively. No dose-dependent effect of CVT-3146 onischemia detection was noted. A conclusion of the study is thatCVT-3146, administered by a logistically simple bolus injection,provides a similar ability to detect and quantify myocardial ischemiawith SPECT MPI as noted with an A infusion.

Example 7

[0208] CVT-3146 is a selective A_(2A) adenosine receptor agonist thatproduces coronary hyperemia and potentially less adverse effects due toits limited stimulation of receptor subtypes not involved with coronaryvasodilation. This study evaluated the effectiveness of CVT-3146 as apharmacologic stress agent.

[0209] 36 subjects (27 men, 9 women; 67±10 years) were studied with twodoses of CVT-3146 [400 mcg (n=8), 500 mcg (n=18)], administered as an IVbolus, as part of a pharmacologic stress myocardial perfusion imagingprotocol.

[0210] Adverse effects (AE) occurred in 26 pts (72%), including chestdiscomfort (33%), headache (25%), and abdominal pain (11%), with asimilar incidence for both doses. Flushing, dyspnea, and dizziness weremore frequent in the 500-mcg group (44%, 44%, and 28%, respectively)than in the 400-mcg group (17%, 17%, and 11%, respectively). Most AEswere mild to moderate (96%) and resolved within 15 min without treatment(91%). One serious AE occurred, with exacerbation of a migraineheadache, which required hospitalization. ST and T wave abnormalitiesdeveloped with CVT-3146 in 7 and 5 pts, respectively. No 2nd or 3rddegree AV block was noted and there were no serious arrhythmias. Peakhemodynamic effects are shown in Table 3 and were noted at 4 min forsystolic blood pressure (BP), 8 min for diastolic BP, and within 2 minfor heart rate (HR). The effect on BP was minimal and systolic BP didnot fall below 90 mmHg with either dose. The mean change in HR responsewas higher for the 500 mcg dose (44.2%) than for 400 mcg (34.8%;p=n.s.). Thirty min after CVT-3146, BP changes deviated <2% frombaseline but HR remained above baseline by 8.6%.

[0211] The results of this study indicate that CVT-3146 iswell-tolerated and has acceptable hemodynamic effects. Minimaldifferences were noted in BP and HR responses between the 400 mcg and500 mcg doses, but AEs were more frequently at the higher dose. CVT-3146appears safe and well-tolerated for bolus-mediated pharmacologic stressperfusion imaging. Hemodynamic Changes (mean±S.D.) TABLE 3 AbsoluteChange Relative Change Heart Rate +21.9 ± 10.4 beats per min +36.7% ±21.0% Systolic BP −5.9 ± 10.7 mmHg −4.1% ± 7.6% Diastolic BP −5.4 ± 7.2mmHg −7.9% ± 10.5%

Example 8

[0212] In this study the vasodilator effects of CVT-3146 were comparedto those of ADO in different vascular beds in awake dogs. Dogs werechronically instrumented for measurements of the blood flow in coronary(CBF), mesenteric (MBF), hind limb (LBF), and renal (RBF) vascular beds,and hemodynamics. Bolus injections (iv) to CVT-3146 (0.1 to 2.5 μg/kg)and ADO (10 to 250 μg/kg) caused significant increases in CBF (35±6 to205±23% and 58±13 to 163±16%) and MBF (18±4 to 88±14% and 36±8 to84±5%).

[0213] The results of the study demonstrate that CVT-3146 is a morepotent and longer lasting coronary vasodilator compared to ADO (theduration for CBF above 2-fold of the baseline; CVT-3146 (2.5 μg/kg):130±19s; ADO (250 μg/kg): 16±3s, P<0.5). As shown in FIG. 18 (mean±SE,n=6), CVT-3146 caused a smaller increase in LBF than ADO. ADO caused adose-dependent renal vasoconstriction (RBF −46−7 to −85±4%), whereasCVT-3146 has no or a little effect on RBF (−5±2 to −11±4%, P<0.05,compared to ADO). In conclusion, CVT-3146 is a more selective and potentcoronary vasodilator than ADO. CVT-3146 has no the significant effect onrenal blood flow in awake dogs. These features of CVT-3146 make it anideal candidate for radionuclide myocardial perfusion imaging.

[0214] The invention now having been fully described, it will beapparent to one of ordinary skill in the art that many changes andmodifications can be made thereto without departing from the spirit orscope of the invention.

What is claimed is:
 1. A method of producing coronary vasodilationwithout peripheral vasodilation comprising administering at least 10 μgof at least one A_(2A) receptor agonist to a human.
 2. The method ofclaim 1 wherein the A_(2A) receptor agonist is administered in an amountthat does not exceed about 1000 μg.
 3. The method of claim 1 wherein theA_(2A) receptor agonist is administered in an amount ranging from about10 to about 600 μg.
 4. The method of claim 1 wherein the A_(2A) receptoragonist is administered in a single dose.
 5. The method of claim 1wherein the A_(2A) receptor agonist is administered by iv bolus.
 6. Themethod of claim 1 wherein the A_(2A) receptor agonist is administered inan amount ranging from about 0.05 to about 60 μg/kg and wherein theA_(2A) receptor agonist is administered by iv bolus.
 7. The method ofclaim 1 wherein the A_(2A) receptor agonist is administered in an amountranging from about 0.1 to about 30 μg/kg wherein the A_(2A) receptoragonist is administered by iv bolus.
 8. The method of claim 1 whereinthe A_(2A) receptor agonist is administered in an amount no greater thanabout 20 μg/kg to a supine patient and wherein the A_(2A) receptoragonist is administered by iv bolus.
 9. The method of claim 1 whereinthe A_(2A) receptor agonist is administered in an amount no greater thanabout 10 μg/kg to a standing patient wherein the A_(2A) receptor agonistis administered by iv bolus.
 10. The method of claim 1 wherein theA_(2A) receptor agonist is administered in an amount ranging from about10 to about 600 μg wherein the wherein the A_(2A) receptor agonist isadministered in about 20 seconds.
 11. The method of claim 1 wherein theA_(2A) receptor agonist is administered in an amount ranging from about10 to about 600 μg wherein the A_(2A) receptor agonist is administeredin less than about 10 seconds.
 12. The method of claim 1 wherein theA_(2A) receptor agonist is administered in an amount greater than about100 μg.
 13. The method of claim 1 wherein the A_(2A) receptor agonist isadministered in an amount no greater than 600 μ.
 14. The method of claim1 wherein the A_(2A) receptor agonist is administered in an amount nogreater than 500 μg.
 15. The method of claim 1 wherein the A_(2A)receptor agonist is administered in an amount ranging from about 100 μgto about 500 μg.
 16. The method of claim 1 wherein the A_(2A) receptoragonist is selected from the group consisting of CVT-3033, CVT-3146 andcombinations thereof.
 17. A method of myocardial perfusion imaging of ahuman, comprising administering a radionuclide and a A_(2A) receptoragonist to the human wherein the myocardium is examined for areas ofinsufficient blood flow following administration of the radionuclide andthe A_(2A) receptor agonist.
 18. The method of claim 17 wherein themyocardium examination begins within about 1 minute from the time theA_(2A) receptor agonist is administered.
 19. The method of claim 17wherein the administration of the A_(2A) receptor agonist causes atleast a 2.5 fold increase in coronary blood flow.
 20. The method ofclaim 17 wherein the administration of the A_(2A) receptor agonistcauses at least a 2.5 fold increase in coronary blood flow that isachieved within about 1 minute from the administration of the A_(2A)receptor agonist.
 21. The method of claim 17 wherein the radionuclideand the A_(2A) receptor agonist are administered separately.
 22. Themethod of claim 17 wherein the radionuclide and the A_(2A) receptoragonist are administered simultaneously.
 23. The method of claim 17wherein the administration of the A_(2A) receptor agonist causes atleast a 2.5 fold increase in coronary blood flow for less than about 5minutes.
 24. The method of claim 17 wherein the administration of theA_(2A) receptor agonist causes at least a 2.5 fold increase in coronaryblood flow for less than about 3 minutes.
 25. The method of claim 17wherein the A_(2A) receptor agonist is CVT-3146 which is administered inan amount ranging from about 10 to about 600 μg in a single iv bolus.26. The method of claim 25 wherein CVT-3146 is administered in an amountranging from about 100 to about 500 μg in a single iv bolus.
 27. Themethod of claim 17 wherein the a A_(2A) receptor agonist is CVT-3146which is administered in a single dose in an amount ranging from 10 toabout 600 μg that is independent of the weight of the human being dosed.28. The method of claim 27 wherein the dose is administered in about 30seconds or less.
 29. The method of claim 27 wherein the dose isadministered in about 20 seconds or less.
 30. The method of claim 17wherein the A_(2A) receptor agonist is administered in a single dose.